The invention relates to a process for the enantiomer-selective preparation of .gamma.-keto-.delta.-amino acid derivatives of the formula I ##STR5## in which R.sup.1 is an amino-protective group or H,
R.sup.2 is an alkyl group having 1 to 5 C atoms, which can optionally be mono- or di-substituted by --OH, --COOH, --CONH.sub.2 or --NH.sub.2, or in which a CH.sub.2 group can optionally be replaced by --S--, phenyl or cyclohexyl which are unsubstituted or mono- or polysubstituted by alkyl or alkoxy containing 1 to 5 C atoms, halogen, hydroxyl or amino, or phenylalkyl or cylcohexylalkyl, or Het-alkyl, where Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N atoms, which can be fused with a benzene ring, and -alkyl is an alkylene group having 1-5 C atoms, and PA1 R.sup.3 and R.sup.4 in each case independently of one another are H or alkyl having 1-5 atoms.
Compounds of the formula I are used as ketomethylene analogues of a dipeptide and are used as components in inhibitors of angiotensin converting enzyme, described by, for example, R. G. Almquist et al. in J. Med. Chem. 31, 561 (1988), or in tachykinin analogues, described by A. Ewenson et al. in J. Med. Chem. 29, 295 (1986).
The incorporation of these amino acids of the formula I and their reduced forms (.gamma.-hydroxy-.delta.-amino acids) into other pharmacologically interacting peptides, such as, for example, inhibitors of the aspartyl proteases, is also possible.
Hitherto the enantiomer-selective preparation of .gamma.-keto-.delta.-amino acids has been possible only to an unsatisfactory degree. For example, the synthesis of an optically active ketomethylene analogue of the dipeptide L-phenylalanylglycine is described by R. G. Almquist in J. Med. Chem. 23, 1392 (1980). This synthesis is carried out in 6 stages, a N-phthaloyl-L-phenylalanine 2-pyridyl-thioester first being reacted with 2-(2-magnesium-2-bromoethyl)-1,3-dioxolane to give the corresponding ketoacetal (cf. M. Araki et al., Bull. Chem. Soc. Jpn., 47, 1777 (1974) and K. Lloyd et al., J. Chem. Soc.C, 2890 (1971)). The keto group is then converted, analogously to the method of W. S. Johnson et al., J. Am. Chem. Soc., 78, 6289 (1956), to the ethylene ketal, and the phthaloyl group is subsequently subjected to a hydrazinolysis, followed by a benzoylation of the previously formed amine. Then in the 5th and 6th step of the synthesis the compound is first oxidized to the intermediate ketal acid and the ketal group is then removed using trifluoroacetic acid.
Another synthesis is described by A. Ewenson et al. in J. Med. Chem. 29, 295 (1986), in which, however, a mixture of enantiomers is formed.
Since for the effectiveness of such a product the (S)-configuration on the C atom that carries the --NHR.sup.1 group is preferred, an enantiomer-selective synthesis is necessary.
The processes known hitherto have the disadvantage that they are not enantiomer-selective or that numerous time-consuming synthesis steps are necessary.